Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([N+:14]([O-])=O)[C:11]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH2:24][OH:25])=[O:18])=[CH:10][C:9]=1[O:26][CH3:27].[H][H].CCOC(C)=O>C(O)C.[Pd]>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([NH2:14])[C:11]([C:17]([N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH2:24][OH:25])=[O:18])=[CH:10][C:9]=1[O:26][CH3:27]
Reactant: [H][H]
Reactant: COC(=O)CCCOc1cc([N+](=O)[O-])c(C(=O)N2CCCC2CO)cc1OC
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)CCCOc1cc(N)c(C(=O)N2CCCC2CO)cc1OC

Procedure:
The nitro ester 14 (38.4 g, 97 mmol) was dissolved in ethanol (2 batches of 19.2 g in 200 mL ethanol per 500 mL hydrogenation flask). 10% Pd/C was added as a slurry in ethanol (1 g per batch) and the mixture was hydrogenated in a Parr hydrogenation apparatus at 40 psi until no further hydrogen uptake was observed. Reaction completion was confirmed by TLC analysis (EtOAc) and the mixture was filtered through celite. The solvent was removed in vacuo and the amine 15 was used directly in the next step. (35.4 g, quantitative yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]OC)=[N:5][N:4]=[C:3]1[SH:10].[C:11](O)(=O)CC.CNC(=S)NN>>[CH3:1][N:2]1[C:6]([CH2:7][CH3:11])=[N:5][N:4]=[C:3]1[SH:10]
Reactant: COCc1nnc(S)n1C
Reactant: CCC(=O)O
Agent: CNC(=S)NN
Product: CCc1nnc(S)n1C

Procedure:
The reaction was performed similar to the method described for the preparation 4-Methyl-5-methoxymethyl-4H-[1,2,4]triazole-3-thiol by reacting 16.4 g of N,N′-carbonyldiimidazol (0.101 mol) with 5 g of propionic acid (0.067 mol) and 14.2 g of 4-methyl-3-thiosemicarbazid (0.135 mol). Yield: 3.8 g
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]2[CH:23]=[CH:22][C:21]([CH2:24][N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[CH:20][N:8]2[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.O.[NH2:32][NH2:33]>CO>[CH2:12]([O:11][C:10]1[C:9](=[O:19])[N:8]2[CH:20]=[C:21]([CH2:24][N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[CH:22]=[CH:23][C:7]2=[N:6][C:5]=1[C:3]([NH:32][NH2:33])=[O:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: COC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc2ccc(CN3CCOCC3)cn2c(=O)c1OCc1ccccc1
Reaction time: 1 h
Yield: 80.8 %

Procedure:
To a solution of 3-benzyloxy-7-morpholin-4-ylmethyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-2-carboxylic acid methyl ester (AU2007001980) (1 g, 2.44 mmol) in methanol (15 ml), hydrazine hydrate (1.44 g, 85% content, 24.4 mmol) was added at room temperature. The mixture was stirred for 1 hour. After most of the solvent was evaporated under reduced pressure, 15 ml of water was added. The mixture was extracted with dichloromethane three times, and the extracts were washed with brine, dried over anhydrous sodium sulfate and concentrated to dryness to give the titled product (807 mg, 80.7%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[C:16]([O:20][C:21]([N:23]1[CH2:27][C@H:26]([CH3:28])OS1(=O)=O)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([C@H:26]([CH3:28])[CH2:27][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([CH3:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C)ccc2[nH]1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Product: CCOC(=O)c1cc2cc(C)ccc2n1[C@H](C)CNC(=O)OC(C)(C)C

Procedure:
The title compound was prepared in accordance with the general method of example 12b) from 5-methyl-1H-indole-2-carboxylic acid ethyl ester and (S)-5-methyl-2,2-dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=3)=[N:11][C:10]=2[C:23]([OH:25])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:30][C:31]1[S:32][CH:33]=[N:34][N:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)=[N:11][C:10]=2[C:23]([NH:30][C:31]2[S:32][CH:33]=[N:34][N:35]=2)=[O:25])=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)O)cc1
Reactant: Nc1nncs1
Solvent: O=S(Cl)Cl
Product: COc1ccc(-c2[nH]c(-c3ccc([N+](=O)[O-])cc3)nc2C(=O)Nc2nncs2)cc1

Procedure:
5-(4-Methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid, 1 M hydrochloric acid—ether solution, thionyl chloride and 2-amino-1,3,4-thiadiazole are reacted and treated in the same manner as in Example 1 to give 5-(4-methoxyphenyl)-2-(4-nitrophenyl)-N-(1,3,4-thiadiazol-2-yl)imidazole-4-carboxamide.
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([CH3:6])=[O:5].[H-].[Na+].[C:9](#[N:13])[CH:10]([CH3:12])[CH3:11].C(Cl)Cl>O1CCCC1.O>[CH3:6][S:4]([C:3]([S:2][CH3:1])=[C:9]([NH2:13])[CH:10]([CH3:12])[CH3:11])=[O:5]
Reactant: CC(C)C#N
Reactant: CSCS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CSC(=C(N)C(C)C)S(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1.20 Grams of methyl methylthiomethyl sulfoxide was dissolved in 10 ml of tetrahydrofuran (THF), and to which 250 mg of sodium hydride was added under cooling with ice. Then the system was stirred for 30 minutes at room temperature. Subsequently, 1.25 ml of isobutyronitrile was added, followed by 13 hours' stirring at room temperature, further addition of 50 ml of methylene chloride and 1 ml of water, and additional 30 minutes' stirring at room temperature. After drying with Glauber's salt, the reaction mixture was concentrated under reduced pressure to provide a light yellow, crystalline product. Recrystallizing (washing) the same from carbon tetrachloride and cyclohexane, 682 mg of 1-methylsulfinyl-1-methylthio-2-amino-3-methyl-1-butene was obtained as a light yellow solid. The mother liquor was passed through a column chromatography (silica gel, methylene chloride, ethyl acetate, and methanol) to yield 672 mg of a mixture of methyl methylthiomethyl sulfoxide with 1-methylsulfinyl-1-methylthio-2-amino-3-methyl-1-butene as a light yellow oil, which was confirmed to be a mixture of 575 mg of methyl methylthiomethyl sulfoxide and 97 mg of 1-methylsulfinyl-1-methylthio-2-amino-3-methyl-1-butene, upon NMR quantitative analysis. The latter's isolation yield was 41.7%, and the conversion yield was 80.2%. The sample for the analysis was obtained by recrystallizing the product from chloroform-n-hexane.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Pb].[CH3:5][C:6]1[N:7]=[CH:8][NH:9][C:10]=1[CH2:11][S:12][CH2:13][CH2:14][NH:15][C:16]([NH2:18])=S.[CH3:19][N:20](C)C=O>C(#N)C>[C:2]([NH:3][C:16]([NH:18][CH3:19])=[N:15][CH2:14][CH2:13][S:12][CH2:11][C:10]1[NH:9][CH:8]=[N:7][C:6]=1[CH3:5])#[N:1].[NH2:1][C:2]([NH2:20])=[NH:3]
Reactant: Cc1nc[nH]c1CSCCNC(N)=S
Reactant: CN(C)C=O
Reactant: N#CN
Agent: [Pb]
Solvent: CC#N
Product: CNC(=NCCSCc1[nH]cnc1C)NC#N
Product: N=C(N)N
Reaction time: 24 h

Procedure:
Lead cyanamide (3.0 g.) was added to a solution of N-methyl-N'-[2-((4-methyl-5-imidazolyl)methylthio)ethylthiourea (2.44 g.) in acetonitrile (50 ml.). Dimethylformamide (20 ml.) was added subsequently and the suspension was heated under reflux, with stirring for 24 hours. Filtration, followed by concentration under reduced pressure and purification of the product by chromatography on a column of silica gel with acetonitrile as eluant and recrystallisation from the same solvent afforded N-cyano-N'-methyl-N"-[2-((4-methyl-5-imidazolyl)-methylthio)ethyl]guanidine, methylthio)ethyl]guanidine, m.p. 139°-141°. (Found: C, 47.3; H, 6.6; N, 33.4; S, 12.6. C10N16N6S requires: C, 47.6; H, 6.4; N, 33.3; S, 12.7).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16](Cl)[CH:17]=[CH:18][CH3:19].C([O-])(O)=[O:22].[Na+].Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:16]([O:11][C@H:10]([CH3:12])[C@H:9]([NH:8][C:1]([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2])[C:13]([OH:15])=[O:14])(=[O:22])/[CH:17]=[CH:18]/[CH3:19]
Reactant: CC=CCCl
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C([O-])O
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: C/C=C/C(=O)O[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a solution of Boc-L-Threonine (0.44 g 2.0 mmol) in 10.0 ml of DCM was added crotyl chloride (0.32 g, 3.0 mmol) at RT followed by the addition of catalytic amount of DMAP and TEA (1.0 ml, 6 mmol). The reaction mixture was stirred for 10 h at RT. Aqueous NaHCO3 solution (10 mL) was added to quench the reaction. After 2 hours, 1N HCl aqueous solution was added slowly to PH˜3. The DCM layer was collected and the aqueous was extracted by DCM (2×10 mL). The organic layer was dried over Na2SO4, filterd and the solvent was removed to provide the crude product.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([OH:25])=[C:7]([C:9]2[N:13]([CH:14]3[CH2:17][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]3)[N:12]=[CH:11][CH:10]=2)[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:34][C:35]1[C:36](F)=[CH:37][C:38]([F:61])=[C:39]([S:41]([N:44]([CH2:50][C:51]2[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=2[O:59][CH3:60])[C:45]2[S:46][CH:47]=[N:48][N:49]=2)(=[O:43])=[O:42])[CH:40]=1.C(OC)(C)(C)C>CS(C)=O.O>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:4]=[CH:5][C:6]([O:25][C:36]2[CH:37]=[C:38]([F:61])[C:39]([S:41]([N:44]([CH2:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][CH3:58])=[CH:53][C:52]=3[O:59][CH3:60])[C:45]3[S:46][CH:47]=[N:48][N:49]=3)(=[O:42])=[O:43])=[CH:40][C:35]=2[Cl:34])=[C:7]([C:9]2[N:13]([CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:17]3)[N:12]=[CH:11][CH:10]=2)[CH:8]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: CC(C)(C)OC(=O)N1CC(n2nccc2-c2cc(C(F)(F)F)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: COC(C)(C)C
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3ccc(C(F)(F)F)cc3-c3ccnn3C3CN(C(=O)OC(C)(C)C)C3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.9 %

Procedure:
tert-Butyl 3-[5-(5-trifluoromethyl-2-hydroxyphenyl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (Preparation 34, 400 mg, 1.04 mmol) and potassium carbonate (450 mg, 3.26 mmol) were combined in dimethylsulfoxide (5 mL). To this slurry was added 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-1,3,4-thiadiazol-2-ylbenzenesulfonamide (Preparation 6, 482 mg, 1.04 mmol) and stirred at ambient temperature for 3 hours. tert-Butylmethyl ether (30 mL) and water (30 mL) were added and the layers separated. The organic layer was washed with water (2×30 mL), then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give a foam. The foam was purified by silica gel flash column chromatography (20% to 40% ethyl acetate in heptane gradient elution) to afford the title compound as a colourless foam (600 mg, 70%).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=3)=[CH:20][CH:19]=2)=[C:12]2[C:7]=1[CH2:8][CH2:9][CH2:10][O:11]2.C(O)(C(F)(F)F)=O.[K+].[Br-]>C(#N)C.O>[F:35][C:32]([F:33])([F:34])[C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:21]2[CH:20]=[CH:19][C:18]([CH2:17][S:16][C:13]3[CH:14]=[CH:15][C:6]([O:5][CH2:4][C:3]([OH:36])=[O:2])=[C:7]4[C:12]=3[O:11][CH2:10][CH2:9][CH2:8]4)=[CH:23][CH:22]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)COc1ccc(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)c2c1CCCO2
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=C(O)COc1ccc(SCc2ccc(OCc3ccc(C(F)(F)F)cc3)cc2)c2c1CCCO2

Procedure:
The title compound was prepared in the manner analogous to Example 1 using 83A. mp 143-144° C.; HPLC: area %=96.02, r.t.=3.770 min, γ=214 nm, mobile phase=acetonitrile/water w/0.10% TFA; IR (KBr) cm−1: 3042, 2581, 1739, 1714, 1325, 1116; 400 MHz 1H NMR (DMSO-d6): δ 12.95 (br(s), 1H), 7.66-7.74 (m, 2H), 7.56-7.63 (m, 2H); 7.10-7.17 (m, 2H), 6.92 (d, 1H, J=8.7 Hz), 6.83-6.89 (m, 2H), 6.26 (d, 1H, J=8.5 Hz), 5.13 (s, 2H), 4.58 (s, 2H), 4.08 (t, 2H, J=4.8 Hz), 3.90 (s, 2H), 2.55 (t, 2H, J=6.5 Hz), 1.83 (pentet, 2H); MS m/z 503 (M−1). Anal. Calc'd for C26H23F3O5S: C, 61.90; H, 4.60. found: C, 61.41; H, 4.50.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:20]=[CH:19][C:8]([C:9]([O:11]N2C(=O)CCC2=O)=O)=[CH:7][C:6]=1[CH3:21])=[O:4].[OH:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][NH2:27].C(N(CC)CC)C>CN(C)C=O>[OH:22][C:23]1[CH:24]=[C:25]([CH2:26][NH:27][C:9]([C:8]2[CH:19]=[CH:20][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([CH3:21])[CH:7]=2)=[O:11])[CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1C
Reactant: NCc1cccc(O)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1C
Yield: 91.3 %

Procedure:
A solution of 1-[[4-(methoxycarbonyl)-3-methylbenzoyl]oxy]-2,5-pyrrolidinedione (Example 6; 6.00 g, 20.6 mmol), 3-hydroxybenzylamine (2.92 g, 23.7 mmol) and triethylamine (2.61 g, 25.8 mmol) in N,N-dimethylformamide (100 mL) was stirred at room temperature overnight. The solvent was evaporated (<0.5 mm Hg, 40° C.) and ethyl acetate (200 mL) was added. The solution was washed with 0.5N hydrochloric acid (200 mL), brine (200 mL), saturated sodium bicarbonate solution (2×150 mL) and brine (200 mL). Each aqueous layer was back-extracted in turn with ethyl acetate (100 mL). The combined organic layers were dried (MgSO4), filtered, and evaporated to give 4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]-2-methylbenzoic acid, methyl ester (5.63 g, 91%) as an orange liquid that solidified on standing, mp 100-103° C.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1.[NH2:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:34]([O:41][CH:42]([CH3:58])[CH2:43][C:44]2[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=2)=[CH:33][CH:32]=1>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:23](=[O:24])[NH:30][C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:34]([O:41][CH:42]([CH3:58])[CH2:43][C:44]3[CH:49]=[CH:48][N:47]=[C:46]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:56])[CH3:55])[CH:45]=3)=[CH:33][CH:32]=2)[N:7]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(Cc1ccnc(NC(=O)OC(C)(C)C)c1)Oc1ccc(N)c2ccccc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OC(C)Cc3ccnc(NC(=O)OC(C)(C)C)c3)c3ccccc23)cc1
Reaction time: 16 h
Yield: 40.9 %

Procedure:
A solution of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (5) (212 mg, 0.923 mmol) in DCM (1 mL) was added to a stirred solution of CDI (150 mg, 0.923 mmol) in DCM (1 mL), under nitrogen at RT over 5 min. After 1.5 hr a solution of tert-butyl 4-(2-(4-aminonaphthalen-1-yloxy)propyl)pyridin-2-ylcarbamate (49) (242 mg, 0.615 mmol) in DCM (2 mL) was added and stirring was continued at RT for 16 hr. A second portion of 3-tert-butyl-1-p-tolyl-1H-pyrazol-5-amine (141 mg, 0.615 mmol) in DCM (1 mL) was processed in a similar manner to the first, by reaction with CDI (100 mg, 0.615 mmol) in DCM (1 mL) and the resulting adduct was then added to the reaction mixture. After a further 2.5 hr the mixture was partitioned between water and DCM. The aqueous layer was extracted with DCM and the combined organic extracts were washed with brine and then dried (MgSO4) and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 40 g, 0-100% EtOAc in isohexane, gradient elution) to afford the title compound (50) (163 mg, 40%) as a purple foam: m/z 649 (M+H)+ (ES+).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH2:2][CH:3]=[CH2:4].[OH2:13].C[N+]1([O-])CC[O:18]CC1.[O-]S([O-])(=S)=O.[Na+].[Na+]>CC(C)=O.[Os](=O)(=O)(=O)=O>[OH:13][CH:3]([CH2:4][OH:18])[CH2:2][CH2:1][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1
Reactant: C=CCCc1ccnc(C#N)c1
Reactant: C[N+]1([O-])CCOCC1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(C)=O
Product: N#Cc1cc(CCC(O)CO)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72 %

Procedure:
To a mixed solution of 4-but-3-enyl-pyridine-2-carbonitrile (0.17 g) prepared in (1) in acetone (4 mL)/water (2 mL) were added 4-methylmorpholine N-oxide (0.37 g) and aqueous 4% osmium tetraoxide (0.67 g). The reaction mixture was stirred at RT for 12 hr. Saturated aqueous Na2S2O3 was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and then dried over Na2SO4. The solvent was removed under reduced pressure. The residue was purified by silica gel chromatography (Developing solvent: chloroform/methanol=15/1) to give the title compound (0.15 g, 72%).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C@H:22]([CH2:31][OH:32])[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>N1C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([NH:21][C@H:22]([CH2:31][O:32][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH:16]=[CH:17][C:18]=1[C:19]#[N:20]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C[C@@H](CO)Nc1ccc(C#N)c(Cl)c1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@H](CC(=O)OC(C)(C)C)Nc2ccc(C#N)c(Cl)c2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 86.5 %

Procedure:
p-Toluenesulfonyl chloride (18.2 g, 96 mmol) was added portion-wise to an ice cold solution of 1,1-dimethylethyl (3S)-3-[(3-chloro-4-cyanophenyl)amino]-4-hydroxybutanoate (27.0 g, 87 mmol) in pyridine (75 mL). After stirring at 0° C. for 15 min, ice bath was removed and the reaction was stirred at room temperature for 2.5 h. The reaction was poured into stirred, ice/H2O (400 mL). When the product solidified, it was filtered, and the solid washed well with H2O. The solid was dissolved in EtOAc (350 mL), and washed successively with H2O, aq. citric acid, and H2O. The EtOAc solution was treated with charcoal, dried (MgSO4), filtered, and the solvent evaporated. The crude product was triturated with a mixture of Et2O (150 mL) and petroleum ether (50 mL) to afford the pure product (35.0 g, 87%). 1H-NMR (CDCl3) δ: 1.42 (9H, s), 2.47 (3H, s), 2.60 (2H, m), 4.04 (1H, m), 4.22 (2H, m), 6.45 (1H, dd, J=8 Hz, 4 Hz), 6.56 (1H, d, J=2.4 Hz), 7.35 (3H, m), 7.75 (2H, d, J=8.4 Hz). LC-MS (ES) m/e 465.3 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:11]([OH:13])=[O:12])[CH3:10])=[O:7])[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[Na+].[Na+].[C:20](Cl)([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21]>O.O1CCOCC1>[CH:35]1[C:36]2[CH:24]([CH2:23][O:22][C:20]([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([NH:8][C@@H:9]([CH3:10])[C:11]([OH:13])=[O:12])=[O:7])=[O:21])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]=2[CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)[C@H](N)C(=O)N[C@@H](C)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](C)C(=O)O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 94.5 %

Procedure:
H-Val-Ala-OH 11 (1.0 g, 5.313 mmol, 1.0 eq.) and Na2CO3 (1.42 g, 13.282 mmol, 2.5 eq.) were solubilised in distilled H2O (40 mL) and the mixture was cooled to 0° C. before dioxane (40 mL) was added. Partial precipitation of the amino acid salt occurred. A solution of Fmoc-Cl (1.44 g, 5.579 mmol, 1.05 eq.) dissolved in dioxane (40 mL) was added dropwise with vigorous stirring over 10 minutes. The resulting mixture was stirred at 0° C. for 2 hours before the ice bath was removed and the stirring maintained for 16 hours. The solvent was evaporated under reduced pressure and the solid remaining dissolved in water (450 mL). The pH was adjusted to 2 with 1N HCl (25 mL) and the aqueous layer was subsequently extracted with EtOAc (3×250 mL). The combined organics were washed with brine (100 mL), dried over MgSO4, filtered and the volatiles removed under reduced pressure to afford pure HO-Ala-Val-Fmoc 12 as a white solid (2.06 g, 94%). LC/MS (2.758 min (ES+)), m/z: 411.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 12.47 (br s, 1H), 8.20 (d, 1H, J=6.7 Hz), 7.89 (d, 2H, J=7.5 Hz), 7.75 (t, 2H, J=6.8 Hz), 7.43-7.38 (m, 3H), 7.34-7.30 (m, 2H), 4.31-4.16 (m, 4H), 3.88 (dd, 1H, J=8.8, 7.2 Hz), 1.98 (m, 1H), 1.26 (d, 3H, J=7.3 Hz), 0.89 (d, 3H, J=6.8 Hz), 0.86 (d, 3H, J=6.8 Hz).
Reaction SMILES: [H-].[Na+].[O:3]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5][CH:4]1[CH2:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1.[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C)C=O>[CH2:19]([N:18]1[CH:17]=[CH:16][N:15]=[C:14]1[CH2:13][CH:4]1[O:3][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: c1ccc2c(c1)OCC(Cc1ncc[nH]1)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(Cn2ccnc2CC2COc3ccccc3O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (3.0 g of 50% dispersion in oil) was added to a solution of 2-(1,4-benzodioxan-2-ylmethyl)-imidazole (5.2 g) in dimethylformamide (50 ml) and the resulting mixture was stirred for 30 minutes. The solution was cooled in an ice bath and benzyl bromide (3 ml) was added. After warming to room temperature the mixture was poured into water (250 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, washed with water (3×100 ml), dried over sodium sulfate, and evaporated. The residue was dissolved in methanolic hydrochloric acid and ether was added until an oil came out of solution. The oil was crystallized from isopropanol-ether to give the title compound (2.10 g) as a white powder, m.p. 105°-107° C.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>O.C(O)(=O)C>[OH:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[NH:5][C:2]([NH2:3])=[O:1]
Reactant: Nc1ccccc1O
Reactant: N#C[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)Nc1ccccc1O
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A solution of potassium cyanate (3.94 g, 48.6 mmol) in water (30 mL) was added during 15 min. to suspension of 2-aminophenol (2.41 g, 22.1 mmol) in 50% aqueous acetic acid (160 mL). The resulting solution was allowed to stand at room temperature overnight and then extracted with ethyl ether (3 times). The combined organic extracts was concentrated to small volume and poured into cold saturated aqueous sodium hydrogen carbonate. The solid was filtered and washed with water to afford the subtitle compound (1.61 g, 47.9%).